Recent evidence indicates that extracellular ATP plays an important role in cellular signaling and can act as a neuromodulator in sensory systems. Noxious stimuli, cell damage and certain pathophysiological conditions can evoke release of cytosolic ATP. ATP can bind to either of two purinergic receptors: P2Y G-protein-coupled receptors or P2X ion channel-forming receptors. Through either of these receptor subtypes, ATP is able to evoke an increase in intracellular Ca2+ ([Ca2+]i). [Ca2+]i has a key role in regulating the sensitivity of olfactory signal transduction. Odorants bind to specific receptors on olfactory receptor neurons (ORNs), thereby activating a G-protein coupled adenylyl cyclase/ cAMP second messenger cascade, leading to the sequential opening of cAMP-gated (CNG) cation channels and a large localized influx of [Ca2+]i. The increase in [Ca2+]i plays an important role as a third messenger in olfactory transduction. It opens Ca2+-activated Cl- channels, substantially amplifying the generator current. Calcium increases also mediate odor adaptation through modulation of CNG channel activity or of molecules in the transduction cascade. Thus, changes in [Ca2+]i homeostasis could alter the responsiveness of ORNs to stimuli. This application will test the general hypothesis that noxious or trigeminal nerve stimulation of the peripheral olfactory system evokes the release of ATP that modulates responsiveness of olfactory receptor neurons to odor. It will provide the first detailed molecular, pharmacological, electrophysiological, and immunofluorescence characterization of purinergic nucleotide receptors in peripheral mammalian olfactory structures and will distinguish the role of nucleotides in control, signaling, and modulation of olfaction. Because ATP is released during neurotransmission and by noxious stimuli, these studies may elucidate mechanisms for the observed reduction in olfactory sensitivity during exposure to noxious agents.